Wilms' Tumor gene (WT1 gene) is a gene encoding a zinc-finger transcription factor. In the WT1 gene, it is known that an alternative splicing is occurred at 17 amino-acids site (17AA) composed of an exon 5 in the WT1 gene and at 3 amino-acids site (KTS) existing between a zinc finger 3 and a zinc finger 4 so that four isoforms (17AA(+)KTS(+), 17AA(+)KTS(−), 17AA(−)KTS(+), and 17AA(−)KTS(−)) are generated. All of the four isoforms are expressed in a human solid tumor and a leukemia cell (see Non-Patent Documents 1 and 2, for example).
The WT1 gene had been considered as a tumor suppressor gene. However, it has been found out recently that the WT1 gene functions as an oncogene. For example, the inventors of the present invention have reported that a wild-type WT1 gene that does not include a mutation in itself is highly expressed in almost all the leukemia cells, and a level of the expression has an inverse correlation with prognosis of a leukemia patient (see Non-Patent Documents 3 and 4, for example). It has been also reported by the inventors of the present invention that a growth of the leukemia cell is specifically suppressed by transducing a WT1 antisense DNA into the leukemia cell (see Non-Patent Document 5, for example), and differentiation of a mouse-originated normal myeloid precursor cell and a myeloid precursor cell line 32D c13 into a neutrophil are suppressed by a forced expression of the WT1 gene so as to grow proliferously (see Non-Patent Document 6, for example). Based on these, the inventors of the present invention have indicated that the WT1 gene is responsible for a hematopoietic lineage cell to be leukemic. Moreover, the inventors of the present invention have reported that the wild-type WT1 gene is highly expressed in various solid tumors (see Non-Patent Documents 7 through 14, for example).
The aforementioned four isoforms are considered as having different functions, respectively. For example, WT1 17AA(+)KTS(+) isoform is considered as contributing to a growth of cancer cell (see Non-Patent Document 15). WT1 17AA(+)KTS(−) isoform is considered to be responsible for a formation of a tumor of malignant lymphoma (see Non-Patent Document 16).
In recent years, the inventors of the present invention have shown that siRNA specific to WT1 17AA(+) isoform induces apoptosis of a leukemia cell expressing the WT1 gene (see Non-Patent Document 17).
[Non-Patent Document 1]
    Oji Y. et al., Int. J. Cancer 100: 297 (2002)[Non-Patent Document 2]    Siehl J. M. et al., Ann. Hematol. 83: 745 (2000)[Non-Patent Document 3]    Inoue K. et al., Blood 84: 3071 (1994)[Non-Patent Document 4]    Inoue K. et al., Blood 89: 1405 (1997)[Non-Patent Document 5]    Yamaguchi T. et al., Blood 87: 2828 (1996)[Non-Patent Document 6]    Inoue K. et al., Blood 91: 2969 (1998)[Non-Patent Document 7]    Oji Y. et al., Japanese Journal of Cancer Research 90: 194 (1999)[Non-Patent Document 8]    Oji Y. et al., Int J Cancer; 100: 297-303 (2002)[Non-Patent Document 9]    Ueda T. et al., Cancer Science 94: 271 (2003)[Non-Patent Document 10]    Oji Y. et al., Cancer Science 94: 523 (2003)[Non-Patent Document 11]    Oji Y. et al., Cancer Science 94: 606 (2003)[Non-Patent Document 12]    Oji Y. et al., Cancer Science 94: 712 (2003)[Non-Patent Document 13]    Oji Y. et al., Neoplasma 51: 17 (2004)[Non-Patent Document 14]    Oji Y. et al., Jpn. J. Clin. Oncol. 34: 74 (2004)[Non-Patent Document 15]    Hubinger G. et al., Exp Hematol 10: 1226-1235 (2001)[Non-Patent Document 16]    Li H. et al., Int J Hematol 77: 463-470 (2003)[Non-Patent Document 17]    Ito K. et al., Oncogene; March 6: 1 (2006)[Non-Patent Document 18]    Englert C. et al., Cancer Res 8: 1429-1434 (1997)[Non-Patent Document 19]    Loeb D. M. et al., Leukemia 17: 965-971 (2003)